One major challenge for primary care veterinarians trying to practice evidence-based medicine is the lack of high-quality evidence. Though there are thousands of veterinary research articles published every year, many of them relate to topics of little relevance to general practice. Research on the cutting edge of medicine, which is of interest to academics or suited to advancing academic careers, is often not the most useful for informing primary care.
Due to the paucity of high-quality research evidence, veterinarians are accustomed to using therapies without the support of such data. Therapies suspected to be useful based on pathophysiologic reasoning or clinical experience are often widely used for long periods of time before they are properly tested in controlled research studies, if they ever are. While this is a necessary evil (and we would have few therapies to offer our patients if we were limited only to those for which there was robust research evidence), there are some unfortunate consequences to the situation.
One is that many therapies used extensively for years eventually prove ineffective, or even unsafe, when formally tested. I have written about several examples of such therapies. Tramadol is still widely used as an oral analgesic for dogs despite research evidence showing it to be ineffective.1 There also is serious doubt about the efficacy of glucosamine for osteoarthritis, lysine for viral upper respiratory infections in cats, cranberry extract for urinary tract infections, and many other therapies that have been routinely employed on the basis of low-quality evidence.2–5
Another problem with the routine use of therapies that have not been validated through rigorous scientific testing is veterinarians become accustomed to relying on low-quality evidence, and they may be resistant to abandoning common therapies when higher-quality evidence becomes available showing they are not as effective as believed. The natural difficulty of changing one’s belief about a familiar practice in the face of new evidence means ineffective therapies often persist well past the point at which they have been demonstrated to be ineffective.6–8
The many examples of once widely trusted medical treatments that turned out to be useless or dangerous when properly studied should encourage all of us to limit our confidence in treatments we use that do not have strong supporting scientific evidence, even if they “seem to work” based on personal experience. It also should encourage us to be open-minded about new evidence showing our clinical experiences with specific treatments may not be reliable, and we should be willing to adapt to such evidence and abandon these treatments when the balance of evidence is against them.
Common problem, little research
The latest example of a ubiquitous therapy that has never been properly tested scientifically involves one of the most common clinical problems primary care veterinarians are faced with— diarrhea.9,10 Though the average primary care veterinarian rarely goes a day without seeing a case of acute idiopathic diarrhea, academics and research institutions have not rushed to provide abundant, high-quality research evidence evaluating common treatments for this condition. It is self-limiting, rarely serious, and not the sort of problem one can build an academic career trying to solve. Nevertheless, this condition meaningfully impacts quality of life for many dogs, and their owners, and general practitioners are expected by clients to offer some help. Good evidence showing the effects of common treatments for this condition is needed to support appropriate clinical management of diarrhea.
One recent study has shed some light on one of the oldest and most widely used treatments for acute diarrhea: the antibiotic metronidazole.11,12 This drug has some efficacy against the protozoal parasite Giardia, a common cause of diarrhea, as well as some immunomodulatory activity and effects on the bacterial flora of the gastrointestinal tract.13–21 These properties, along with abundant clinical experience, have long been cited to support the use of metronidazole as a treatment for acute diarrhea. However, there has been little clinical trial research investigating this practice.
Studies show metronidazole is useful in the treatment of canine giardiasis, though estimates of efficacy vary widely.14–19 It has been shown not to add any benefit when combined with prednisone for treatment of inflammatory bowel disease or with amoxicillin-clavulanate for acute hemorrhagic diarrhea.22,23 Until now, however, there have been no placebo-controlled studies specifically testing empirical use of metronidazole for acute idiopathic diarrhea.
In a recent clinical trial, dogs with acute diarrhea and no evidence of a specific underlying cause (e.g. parasitosis, endocrinopathy, organ dysfunction, etc.) were randomized to treatment with metronidazole, a commercial probiotic, or a placebo. Based on owner-reported fecal scores, diarrhea resolved in 4.8 +/- 2.9 days in dogs given the placebo, 4.6 +/- 2.4 days in dogs taking metronidazole, and 3.5 +/- 2.2 days in dogs on the probiotic. The differences between groups were not statistically significant.12
While one study is rarely perfect or definitive evidence for any complex clinical question, this trial does provide strong reason to doubt the value of metronidazole in acute idiopathic diarrhea in dogs. Given the absence of previous controlled research evidence supporting the use of this drug for this problem, it is appropriate to conclude metronidazole is likely ineffective for acute diarrhea and should not be prescribed unless new supporting evidence appears. The temptation to cite clinical experience to justify continued use of metronidazole for this problem should be resisted, as anecdotal evidence is unreliable and inferior to such clinical trial findings.
It is interesting the apparently shorter duration of diarrhea in those dogs given the probiotic was not statistically different from the outcome in the other groups. The authors did report the probiotic deteriorated over time, though there was no apparent difference between subgroups of dogs given the probiotic in the first and second halves of the trial. The study also did not enroll enough dogs for a difference of one day in the duration of diarrhea to reach statistical significance. It is possible the difference of one day, which is large enough to have some clinical impact, might be real and might be statistically significant in a larger study. However, it also is possible the probiotic used in this study simply did not meaningfully affect the clinical course of the subjects and the difference seen was only due to chance.
Previous research evidence evaluating the use of probiotics for diarrhea is mixed.24-32 Some studies show clinically and statistically significant differences in the time to resolution of diarrhea between dogs taking probiotics and placebos, and others do not. The cause of the diarrhea, the probiotic organism used, the dose and form, the viability of specific products, and many other factors likely influence the results of such studies, so while probiotics may have meaningful benefits for acute diarrhea in some cases, the value of particular products in specific patients can be difficult to predict. It is important to remember, as well, that most cases of acute idiopathic diarrhea eventually resolve spontaneously, even in the absence of any treatment.
There has never been strong evidence to support the use of metronidazole to treat acute idiopathic diarrhea for dogs, and the results of the first clinical trial evaluating this practice indicate it is probably not effective. This information should discourage the use of metronidazole as a treatment for acute diarrhea.
In addition, the study found no statistically significant effect of a commercial probiotic on the duration of diarrhea. However,
the existing mixed evidence concerning probiotics and acute diarrhea in dogs does offer some support for the use of these products, though the impact of particular products on individual patients is not reliably predictable. l
Brennen McKenzie, MA, MSc, VMD, cVMA, discovered evidence-based veterinary medicine after attending the University of Pennsylvania School of Veterinary Medicine and working as a small animal general practice veterinarian. He has served as president of the Evidence-Based Veterinary Medicine Association and reaches out to the public through his SkeptVet blog, the Science-Based Medicine blog, and more. He is certified in medical acupuncture for veterinarians. Columnists’ opinions do not necessarily reflect those of Veterinary Practice News.
1 McKenzie BA. Is tramadol an effective analgesic for dogs and cats? Vet Pract News. June 2018:32-33.
2 McKenzie BA. Is cranberry effective for treating UTIs? Vet Pract News. April 2019:38.
3 McKenzie BA. What Is the Evidence ? Glucosamine for osteoarthritis in dogs. J Am Vet Med Assoc. 2010;237(12):1382-1383.
4 McKenzie B. Lysine: A therapeutic zombie? Vet Pract News. May 2018:26-28.
5 Bhathal A, Spryszak M, Louizos C, Frankel G. Glucosamine and chondroitin use in canines for osteoarthritis: A review. Open Vet J. 2017;7(1):36-49. doi:10.4314/ovj.v7i1.6
6 McKenzie BA. Is complementary and alternative medicine compatible with evidence-based medicine? J Am Vet Med Assoc. 2012;241(4). doi:10.2460/javma.241.4.421
7 Mckenzie B. Evidence-based veterinary medicine: What is it and why does it matter? Equine Vet Educ. 2014;26(9). doi:10.1111/eve.12216
8 McKenzie BA. Veterinary clinical decision-making: Cognitive biases, external constraints, and strategies for improvement. J Am Vet Med Assoc. 2014;244(3). doi:10.2460/javma.244.3.271
9 Robinson NJ, Dean RS, Cobb M, Brennan ML. Investigating common clinical presentations in first opinion small animal consultations using direct observation. Vet Rec. 2015;176(18):463-463. doi:10.1136/VR.102751
10 Lund EM, Armstrong PJ, Kirk CA, Kolar LM, Klausner JS. Health status and population characteristics of dogs and cats examined at private veterinary practices in the United States. J Am Vet Med Assoc. 1999;214(9):1336-1341. http://www.ncbi.nlm.nih.gov/pubmed/10319174. Accessed August 16, 2019.
11 German AJ, Halladay LJ, Noble P-JM. First-choice therapy for dogs presenting with diarrhoea in clinical practice. Vet Rec. 2010;167(21):810-814. doi:10.1136/vr.c4090
12 Shmalberg J, Montalbano C, Morelli G, Buckley GJ. A Randomized Double Blinded Placebo-Controlled Clinical Trial of a Probiotic or Metronidazole for Acute Canine Diarrhea. Front Vet Sci. 2019;6:163. doi:10.3389/fvets.2019.00163
13 Faure L, Fournel S, Nicolas C, Rigaut D. A Field Clinical Study to Confirm the Efficacy and Safety of a Metronidazole-based Oral Suspension in Dogs Naturally Infested by Giardiasis: Comparison to Fenbendazole. Int J Appl Res Vet Med. 2018;16(2):110-116. https://jarvm.com/articles/Vol16Iss2/Vol16 Iss2 Nicolas.pdf. Accessed August 16, 2019.
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20 Igarashi H, Maeda S, Ohno K, Horigome A, Odamaki T, Tsujimoto H. Effect of Oral Administration of Metronidazole or Prednisolone on Fecal Microbiota in Dogs. White BA, ed. PLoS One. 2014;9(9):e107909. doi:10.1371/journal.pone.0107909
21 United States Pharmacopeia, American Academy of Veterinary Pharmacology and Therapeutics. Metronidazole USP Drug Monograph.; 2007. https://cdn.ymaws.com/www.aavpt.org/resource/resmgr/imported/metronidazole.pdf. Accessed August 16, 2019.
22 Ortiz V, Klein L, Channell S, et al. Evaluating the effect of metronidazole plus amoxicillin-clavulanate versus amoxicillin-clavulanate alone in canine haemorrhagic diarrhoea: a randomised controlled trial in primary care practice. J Small Anim Pract. 2018;59(7):398-403. doi:10.1111/jsap.12862
23Jergens AE, Crandell J, Morrison JA, et al. Comparison of Oral Prednisone and Prednisone Combined with Metronidazole for Induction Therapy of Canine Inflammatory Bowel Disease: A Randomized-Controlled Trial. J Vet Intern Med. 2010;24(2):269-277. doi:10.1111/j.1939-1676.2009.0447.x
24 Rose L, Rose J, Gosling S, Holmes M. Efficacy of a Probiotic-Prebiotic Supplement on Incidence of Diarrhea in a Dog Shelter: A Randomized, Double-Blind, Placebo-Controlled Trial. J Vet Intern Med. 2017;31(2):377-382. doi:10.1111/jvim.14666
25 Jugan MC, Rudinsky AJ, Parker VJ, Gilor C. Use of probiotics in small animal veterinary medicine. J Am Vet Med Assoc. 2017;250(5):519-528. doi:10.2460/javma.250.5.519
26Wynn SG. Probiotics in veterinary practice. J Am Vet Med Assoc. 2009;234(5):606-613. doi:10.2460/javma.234.5.606
27 Gómez-Gallego C, Junnila J, Männikkö S, et al. A canine-specific probiotic product in treating acute or intermittent diarrhea in dogs: A double-blind placebo-controlled efficacy study. Vet Microbiol. 2016;197:122-128. doi:10.1016/j.vetmic.2016.11.015
28 Herstad HK, Nesheim BB, L’Abée-Lund T, Larsen S, Skancke E. Effects of a probiotic intervention in acute canine gastroenteritis – a controlled clinical trial. J Small Anim Pract. 2010;51(1):34-38. doi:10.1111/j.1748-5827.2009.00853.x
29Delucchi L, Fraga M, Zunino P. Effect of the probiotic Lactobacillus murinus LbP2 on clinical parameters of dogs with distemper-associated diarrhea. http://www.ingentaconnect.com/contentone/cvma/cjvr/2017/00000081/00000002/art00005;jsessionid=3n74gov3pi9u3.x-ic-live-02. Accessed October 29, 2018.
30 Bybee SN, Scorza AV, Lappin MR. Effect of the Probiotic Enterococcus faecium SF68 on Presence of Diarrhea in Cats and Dogs Housed in an Animal Shelter. J Vet Intern Med. 2011;25(4):856-860. doi:10.1111/j.1939-1676.2011.0738.x
31 Kelley RL, Minikhiem D, Kiely B, et al. Clinical benefits of probiotic canine-derived Bifidobacterium animalis strain AHC7 in dogs with acute idiopathic diarrhea. Vet Ther. 2009;10(3):121-130.
32McKenzie BA. Probiotics and today’s pets. Vet Pract News. January 2018:30-31.